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Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2

Author

Listed:
  • Paul Guilhamon

    (Medical Genomics, UCL Cancer Institute, University College London)

  • Malihe Eskandarpour

    (Genetics and Cell Biology of Sarcoma, UCL Cancer Institute, University College London)

  • Dina Halai

    (Royal National Orthopaedic Hospital NHS Trust)

  • Gareth A. Wilson

    (Medical Genomics, UCL Cancer Institute, University College London)

  • Andrew Feber

    (Medical Genomics, UCL Cancer Institute, University College London)

  • Andrew E. Teschendorff

    (Statistical Cancer Genomics, UCL Cancer Institute, University College London)

  • Valenti Gomez

    (Tumour Suppressor Signalling Networks, UCL Cancer Institute, University College London)

  • Alexander Hergovich

    (Tumour Suppressor Signalling Networks, UCL Cancer Institute, University College London)

  • Roberto Tirabosco

    (Royal National Orthopaedic Hospital NHS Trust)

  • M. Fernanda Amary

    (Royal National Orthopaedic Hospital NHS Trust)

  • Daniel Baumhoer

    (Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel)

  • Gernot Jundt

    (Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel)

  • Mark T. Ross

    (Illumina Cambridge Ltd., Chesterford Research Park)

  • Adrienne M. Flanagan

    (Genetics and Cell Biology of Sarcoma, UCL Cancer Institute, University College London
    Royal National Orthopaedic Hospital NHS Trust)

  • Stephan Beck

    (Medical Genomics, UCL Cancer Institute, University College London)

Abstract

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.

Suggested Citation

  • Paul Guilhamon & Malihe Eskandarpour & Dina Halai & Gareth A. Wilson & Andrew Feber & Andrew E. Teschendorff & Valenti Gomez & Alexander Hergovich & Roberto Tirabosco & M. Fernanda Amary & Daniel Baum, 2013. "Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2," Nature Communications, Nature, vol. 4(1), pages 1-9, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3166
    DOI: 10.1038/ncomms3166
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